The Northwestern University (NU) Clinical Research Site (CRS) for the Multicenter AIDS Cohort Study (MACS) addresses the highest research priorities in AIDS research through retention and maintenance of the cohort, collection and repository storage of specimens, and development and implementation of the MACS Research Agenda. Through the leadership we provide and the data and biological specimens we collect, the NU CRS actively contributes to all MACS core protocols and thematic substudies to characterize the long-term, natural and treated history of HIV infection in a cohort of men who report sex with men (MSM). We strictly adhere to good practice guidelines, established policies and procedures, and robust quality assurance and quality control measures to ensure the accuracy, reproducibility, and integrity of the clinical and laboratory data and biological specimens. Scientific and administrative management provides both the flexibility and means to conduct multidisciplinary research projects as well as the resources to respond rapidly to evolving scientific opportunities. For the past 30 years, we have maintained a strong AIDS research portfolio that supports basic discovery research into important priority areas in etiology and pathogenesis, behavior and social science, and natural history and epidemiology. The diversity of the work makes possible a broad and multidisciplinary view of AIDS research. Scientific questions take full advantage of the strengths of the MACS, namely, its duration and the continuity of data and specimens that timespan provides. Researchers can distinguish data and specimens from men before and after infection, before and after beginning medications, or before and after the development of comorbidities or their complications. Productive relationships across the entire MACS consortium, as well as other consortia and organizations, have coalesced around specific issues to advance scientific knowledge, the health of people, and policy development. By capitalizing on the unique resources of the NU Genome Sequencing and Analysis Program, we are able to explore the human genome and define the biological circuits that underlie cellular processes in search of the molecular basis of disease. MACS genomic data are shared among investigators in an interpretable manner and made widely available to the research community through a controlled-access system that reduces the risks of sharing potentially identifying data. Looking ahead, the NU CRS will continue to support a rational, holistic research plan that will provide insight into the evolving biological and psychosocial characteristics of the HIV/AIDS epidemic in MSM. We will build upon our AIDS research portfolio built on a unique cohort, rich with clinical and biological information. We will replace existing cohort members who die or are lost to follow-up using a rolling cohort design. With data obtained through multidisciplinary studies of high scientific quality, we expect to advance research that will help to better manage the care and treatment of people living with HIV/AIDS, and contribute to vaccine development as well as public health policy and interventions.